Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g., Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter""s syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic xcex2 cells.
Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985), reviews the biological activities which have been attributed to IL-1. It should be noted that some of these effects have been described by others as indirect effects of IL-1.
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, altograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn""s disease, ulcerative colitis, or pyresis.
AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. Other viruses, such as HIV-1, HIV-2 infect T lymphocytes after T Cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication. Monokines, specifically TNF, are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with monokine activity such as by inhibition of monokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T-cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, (1989)]. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli, et al., Proc. Natl. Acad. Sci., 87:782-784 (1990)], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T-cells.
TNF has also been implicated in various roles with other viral infections, such as the cytomegalia virus (CMV), influenza virus, and the herpes virus for similar reasons as those noted.
Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. IL-8 is produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and ketainocytes. Its production from endothelidl cells is induced by IL-1, TNF, or lipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse, Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have been applied to IL-8, such as neutophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutophils, T-lymphocutes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothellal cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increased in IL-8 production (which is responsible for chemotaxis of neutophils into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.
IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
There remains a need for treatment, in this field, for compounds which are cytokine suppressive anti-inflammatory drugs, i.e. compounds which are capable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.
This invention relates to the novel compounds of Formula (I) and pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable diluent or carrier.
This invention also relates to a method of inhibiting cytokines and the treatment of a cytokine mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
This invention more specifically relates to a method of inhibiting the production of IL-1 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
This invention more specifically relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
This invention more specifically relates to a method of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
Accordingly, the present invention provides a compound of formula (I): 
wherein:
R1 is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolinyl, 1-imidazolyl or 1-benzimidazolyl which is optionally substituted with one or two substituents each of which is independently selected from C1-4 alkyl, halogen, C1-4 alkoxy, C1-4 alkylthio, NH2, mono- or di-C1-6-alkylamino or N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR22;
R2 is hydrogen, C1-10 alkyl N3, xe2x80x94(CR10R20)nOR12, heterocyclyl, heterocyclylC1-10 alkyl, C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkylC1-10alkyl, C5-7 cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, (CR10R20)nxe2x80x2OR13, (CR10R20)nxe2x80x2S(O)mR25, (CR10R20)nxe2x80x2NHS(O)2R25, (CR10R20)nxe2x80x2NR8R9, (CR10R20)nxe2x80x2NO2, (CR10R20)nxe2x80x2CN, (CR10R20)nxe2x80x2SO2R25, (CR10R20)nxe2x80x2S(O)mNR8R9, (CR10R20)nxe2x80x2C(Z)R13, (CR10R20)nxe2x80x2C(Z)OR13, (CR10R20)nxe2x80x2C(Z)NR8R9, (CR10R20)nxe2x80x2C(Z)NR13OR12, (CR10R20)nxe2x80x2NR10C(Z)R13, (CR10R20)nxe2x80x2NR10C(Z)NR8R9, (CR10R20)nxe2x80x2N(OR21)C(Z)NR8R9, (CR10R20)nxe2x80x2N(OR21)C(Z)R13, (CR10R20)nxe2x80x2C(xe2x95x90NOR21)R13, (CR10R20)nxe2x80x2NR10C(xe2x95x90NR27)NR8R9, (CR10R20)nxe2x80x2OC(Z)NR8R9, (CR10R20)nxe2x80x2NR10C(Z)NR8R9, (CR10R20)nxe2x80x2NR10C(Z)OR10, 5-(R25)-1,2,4-oxadizaol-3-yl or 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl moieties may be optionally substituted;
nxe2x80x2 is an integer having a value of 1 to 10;
m is 0, or the integer 1 or 2;
R3 is xe2x80x94XaP(Z)(XbR13)2 or Q-(Y1)t;
Q is an aryl or heteroaryl group;
t is a number having a value of 1, 2 or 3;
Xa is xe2x80x94NR8xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or a C1-10 alkylene chain optionally substituted by C1-4 alkyl and optionally interrupted by xe2x80x94NR8xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
Xb is xe2x80x94(CR10R20)n, xe2x80x94NR8xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
Z is oxygen or sulfur;
n is 0 or an integer from 1 to 10;
Y1 is independently selected from hydrogen, C1-5 alkyl, halo-substituted C1-5 alkyl, halogen, xe2x80x94Xaxe2x80x94P(Z)xe2x80x94(XbR13)2 or xe2x80x94(CR10R20)nY2;
Y2 is xe2x80x94OR8, xe2x80x94NO2, xe2x80x94S(O)mxe2x80x3R11, xe2x80x94SR8, xe2x80x94S(O)mxe2x80x3OR8, xe2x80x94S(O)mNR8R9, xe2x80x94NR8R9, xe2x80x94O(CR10R20)nxe2x80x2NR8R9, xe2x80x94C(O)R8, xe2x80x94CO2R8, xe2x80x94CO2(CR10R20)nxe2x80x2CONR8R9, xe2x80x94ZC(O)R8, xe2x80x94CN, xe2x80x94C(Z)NR8R9, xe2x80x94NR10C(Z)R8, xe2x80x94C(Z)NR8OR9, xe2x80x94NR10C(Z)NR8R9, xe2x80x94NR10S(O)mxe2x80x2R11, xe2x80x94N(OR21)C(Z)NR8R9, xe2x80x94N(OR21)C(Z)R8, xe2x80x94C(xe2x95x90NOR21)R8, xe2x80x94NR10C(xe2x95x90NR15)SR11, xe2x80x94NR10C(xe2x95x90NR15)NR8R9, xe2x80x94NR10C(xe2x95x90CR14R24)SR11, xe2x80x94NR10C(xe2x95x90CR14R24)NR8R9, xe2x80x94NR10C(O)C(O)NR8R9, xe2x80x94NR10C(O)C(O)OR10, xe2x80x94C(xe2x95x90NR13)NR8R9, xe2x80x94C(xe2x95x90NOR13)NR8R9, xe2x80x94C(xe2x95x90NR13)ZR11, xe2x80x94OC(Z)NR8R9, xe2x80x94NR10S(O)mxe2x80x3CF3, xe2x80x94NR10C(Z)OR10, 5-(R18)-1,2,4-oxadizaol-3-yl or 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl;
mxe2x80x3 is a number having a value of 1 or 2;
R4 is phenyl, naphth-1-yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substitiuent, is halo, cyano, xe2x80x94C(Z)NR7R17, xe2x80x94C(Z)OR23, xe2x80x94(CR10R20)mxe2x80x2xe2x80x3COR36, SR5, xe2x80x94SOR5, xe2x80x94OR36, halo-substituted-C1-4 alkyl, C1-4 alkyl, xe2x80x94ZC(Z)R36, xe2x80x94NR10C(Z)R23, or xe2x80x94(CR10R20)mxe2x80x2xe2x80x3NR10R20 and which, for other positions of substitution, is halo, cyano, xe2x80x94C(Z)NR16R26, xe2x80x94C(Z)OR8, xe2x80x94(CR10R20)mxe2x80x3COR8, xe2x80x94S(O)mR8, xe2x80x94OR8, halo-substituted-C1-4 alkyl, xe2x80x94C1-4 alkyl, xe2x80x94(CR10R20)mxe2x80x2NR10C(Z)R8, xe2x80x94NR10S(O)mxe2x80x2R11, xe2x80x94NR10S(O)mxe2x80x2NR7R17 xe2x80x94ZC(Z)R8 or xe2x80x94(CR10R20)mxe2x80x2NR16R26; wherein mxe2x80x3 is 0 to 5 and mxe2x80x2xe2x80x3 is 0 or 1;
R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties xe2x80x94SR5 being xe2x80x94SNR7R17 and xe2x80x94SOR5 being xe2x80x94SOH;
R6 is C1-4 alkyl, halo-substituted-C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or C3-5 cycloalkyl;
R7 and R17 is each independently selected from hydrogen or C1-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR22;
R8 is hydrogen, heterocyclyl, heterocyclylalkyl or R11;
R9 is hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R8 and R9 may together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12;
R10 and R20 is each independently selected from hydrogen or C1-4 alkyl;
R11 is C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R12 is hydrogen, xe2x80x94C(Z)R13 or optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted arylC1-4 alkyl, or S(O)2R25;
R13 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclylC1-10 alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroaryl C1-10 alkyl;
R14 and R24 is each independently selected from hydrogen, alkyl, nitro or cyano;
R15 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl;
R16 and R26 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12;
R18 and R19 is each independently selected from hydrogen, C1-4 alkyl, substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl or together denote a oxygen or sulfur;
R21 is hydrogen, a pharmaceutically acceptable cation, C1-10 alkyl, C3-7 cycloalkyl, aryl, aryl C1-4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or C1-10 alkanoyl;
R22 is R10 or C(Z)xe2x80x94C14 alkyl;
R23 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-5 cycloalkyl;
R36 is hydrogen or R23;
R25 is C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10alkyl, heteroaryl or heteroarylalkyl;
R27 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl, or aryl;
or a pharmaceutically acceptable salt thereof;
and excluding 2-(4-chlorophenyl)-4-(4-methoxyphenyl)-5-(4-pyridyl)imidazole, and 2-phenyl-4-phenyl-5-(4-pyridyl)imidazole.
The novel compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of cytokine inhibition or production. In particular, cytokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section, but in particular viral infections. Examples of such viruses include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retovirus infections, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.
In Formula (I), suitable R1 moieties includes 4-pyridyl, 4-pyrimidinyl, 4-quinolyl, 6-isoquinolinyl, quinazolin-4-yl, 1-imidazolyl and 1-benzimidazolyl, of which 4-pyridyl, 4-pyrimidinyl and 4-quinolyl, are preferred. More preferably R1 is a 4-pyridyl or 4-pyrimidinyl group. A preferred substituent for all R1 moieties is C1-4 alkyl, in particular methyl, and NR10R20, preferably where R10 and R20 are hydrogen or methyl, more preferably R10 and R20 are hydrogen. A more preferred substituent is the NR10R20 moiety. Preferred ring placement of the R1 substituent on the 4-pyridyl derivative is the 2-position, such as 2-methyl-4-pyridyl. Preferred ring placement on the 4-pyrimidinyl is also at the 2-position, such as 2-methyl-pyrimidine or 2-amino-pyrimidine.
Suitably, R2 is hydrogen, xe2x80x94(CR10R20)n OR12, heterocyclyl, heterocyclylC1-10 alkyl, C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkylC1-4 alkyl, C5-7 cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, (CR10R20)nxe2x80x2OR13, (CR10R20)nxe2x80x2S(O)mR25, (CR10 R20)nxe2x80x2NHS(O)2R25, (CR10R20)nxe2x80x2NR8R9, (CR10R20)nxe2x80x2NO2, (CR10R20)nxe2x80x2CN, (CR10R20)nxe2x80x2SO2R25, (CR10R20)nxe2x80x2S(O)mNR8R9, (CR10R20)nxe2x80x2C(Z)R13, (CR10R20)nxe2x80x2C(Z)OR13, (CR10R20)nxe2x80x2C(Z)NR8R9, (CR10R20)nxe2x80x2C(Z)NR13OR12, (CR10R20)nxe2x80x2NR10C(Z)R13, (CR10R20)nxe2x80x2NR10C(Z)NR8R9, (CR10R20)nxe2x80x2N(OR21)C(Z)NR8R9, (CR10R20)nxe2x80x2N(OR21)C(Z)R13, (CR10R20)nxe2x80x2C(xe2x95x90NOR21)R13, (CR10R20)nxe2x80x2NR10C(xe2x95x90NR27)NR8R9, (CR10R20)nxe2x80x2OC(Z)NR8R9, (CR10R20)nxe2x80x2NR10C(Z)NR8R9, (CR10R20)nxe2x80x2NR10C(Z)OR10, 5-(R25)-1,2,4-oxadizaol-3-yl or 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl moieties may be optionally substituted.
Preferably R2 is hydrogen, an optionally substituted heterocyclyl ring, and optionally substituted heterocyclylC1-10 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted C3-7cycloalkyl, an optionally substituted C3-7cycloalkyl C1-10 alkyl, (CR10R20)nxe2x80x2C(Z)OR13 group, (CR10R20)nxe2x80x2NR8R9, (CR10R20)nxe2x80x2NHS(O)2R25, (CR10R20)nxe2x80x2S(O)mR25, an optionally substituted aryl; an optionally substituted arylC1-10 alkyl, (CR10R20)nxe2x80x2OR13, (CR10R20)nxe2x80x2C(Z)R13, or (CR10R20)nxe2x80x2C(xe2x95x90NOR21)R13.
More preferably R2 is an optionally substituted C1-10 alkyl, an optionally substituted heterocyclyl ring, an optionally substituted heterocyclylC1-10 alkyl, an optionally substituted aryl, (CR10R20)nxe2x80x2NR8R9, or (CR10R20)nxe2x80x2C(Z)OR13 group
When R2 is an optionally substituted heterocyclyl the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group. When the ring is optionally substituted the substituents may be directly attached to the free nitrogen, such as in the piperidinyl group or pyrrole ring, or on the ring itself. Preferably the ring is a piperidine or pyrrole, more preferably piperidine. The heterocyclyl ring may be optionally substituted one to four times independently by halogen; C1-4 alkyl; aryl, such as phenyl; aryl alkyl, such as benzylxe2x80x94wherein the aryl or aryl alkyl moieties themselves may be optionally substituted (as in the definition section below); C(O)OR13, such as the C(O)C1-4 alkyl or C(O)OH moieties; C(O)H; C(O)C1-4 alkyl, hydroxy substituted C1-4 alkyl, C1-4 alkoxy, S(O)mC1-4 alkyl (wherein m is 0, 1, or 2), NR10R20 (wherein R10 and R20 are independently hydrogen or C1-4 alkyl).
Preferably if the ring is a piperidine, the ring is attached to the imidazole at the 4-position, and the substituents are directly on the available nitrogen, i.e. a 1-Formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine, 1-ethoxycarbonyl-4-piperidine. If the ring is substituted by an alkyl group and the ring is attached in the 4-position, it is preferably substituted in the 2 or 6 position or both, such as 2,2,6,6-tetramethyl-4-piperidine. Similarly, if the ring is a pyrrole, the ring is attached to the imidazole at the 3-position, and the substituents are also directly on the available nitrogen.
When R2 is an optionally substituted heterocyclyl C1-10 alkyl group, the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group. Preferably this alkyl moiety is from 1 to 4, more preferably 3 or 4, and most preferably 3, such as in a propyl group. Preferred heterocyclic alkyl groups include but are not limited to, morpholino ethyl, morpholino propyl, pyrrollidinyl propyl, and piperidinyl propyl moieties. The heterocyclic ring herein is also optionally substituted in a similar manner to that indicated above for the direct attachment of the heterocyclyl.
When R2 is an optionally substituted C3-7 cycloalkyl, or an optionally substituted C3-7cycloalkyl C1-10 alkyl, the cycloalkyl group is preferably a C5 to C6 ring which ring may be optionally substituted one or more times independently by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; C1-10 alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1, or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl; amino, mono and di-substituted amino, such as in the NR7R17 group; or where the R7R17 may cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S; C1-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted alkyl, such as CF3; hydroxy substituted C1-10 alkyl; C(O)OR13, such as the free acid or methyl ester derivative; an optionally substituted aryl, such as phenyl; an optionally substituted arylalkyl, such as benzyl or phenethyl; and further where these aryl or aryl alkyl moieties may also be substituted one to two times by halogen; hydroxy; C1-10 alkoxy; S(O)m alkyl; amino, mono and di-substituted amino, such as in the NR7R17 group; alkyl or halosubstituted alkyl.
When R2 is (CR10R20)nxe2x80x2NR8R9, R8 and R9 are as defined in Formula (I), preferably R8 and R9 are each independently selected from hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl or an optionally substituted aryl-C1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12. It is recognized that in some instances this can yield the same moiety as a heterocyclic C1-10 alkyl moiety noted above which is also a suitable R2 variable. Preferably R8 and R9 are independently hydrogen, C1-4 alkyl, preferably methyl, or benzyl. The n term is preferably 1 to 4, more preferably 3 or 4, and most preferably 3, such as in a propyl group. Preferred groups include, but are not limited to, aminopropyl, (N-methyl-N-benzyl)aminopropyl, (N-Phenyl-methyl)amino-1-propyl, or diethylamino propyl.
When R2 is a (CR10R20)nxe2x80x2C(Z)OR13 group, R13 is suitably hydrogen, C1-4 alkyl, especially methyl. The nxe2x80x2 term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group. Preferred groups include, but are not limited to, carboxymethyl-1-butyl, carboxy-1-propyl, or 2-acetoxyethyl.
When R2 is a (CR10R20)nxe2x80x2S(O)mR25 group m is 0, 1, or 2, and R18 is preferably aryl, especially phenyl, or C1-10 alkyl, especially methyl. The n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group.
When R2 is a (CR10R20)nxe2x80x2OR13 group, R13 is suitably hydrogen, aryl, especially phenyl, or C1-10 alkyl, especially methyl or ethyl. The n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group.
When R2 is a (CR10R20)nxe2x80x2NHS(O)2R25 group, R25 is suitably alkyl, especially methyl. The n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group.
When R2 is a optionally substituted aryl, the aryl is preferably phenyl. The aryl ring may be optionally substituted one or more times, preferably by one or two substituents, independently selected from C1-4 alkyl, halogen, especially fluoro or chloro, (CR10R20)tOR13, (wherein t is 0, or an integer of 1 to 4), xe2x80x94(CR10R20)tNR10 R20, especially amino or mono- or di-alkylamino xe2x80x94(CR10R20)tS(O)mR25, wherein m is 0, 1 or 2; xe2x80x94SHxe2x80x94, xe2x80x94(CR10R20)nxe2x80x94NR8R9, xe2x80x94NR10C(Z)R8 (such xe2x80x94NHCO(C1-10 alkyl)); xe2x80x94NR10S(O)mR25(such as xe2x80x94NHSO2(C1-10 alkyl)). Preferably the phenyl is substituted in the 3 or 4-position by xe2x80x94(CR10 R20)tS(O)mR25, and R25 is preferably C1-10 alkyl, especially methyl.
When R2 is an optionally substituted heteroaryl or heteroarylalkyl group the ring may be optionally substituted one or more times, preferably by one or two substituents, independently selected from one or more times, by C1-4 alkyl, halogen, especially fluoro or chloro, (CR10R20)tOR13, xe2x80x94(CR10R20)tNR10R20, especially amino or mono- or di-alkylamino xe2x80x94(CR10R20)tS(O)mR25, wherein m is 0, 1 or 2; xe2x80x94SHxe2x80x94, xe2x80x94(CR10R20)nxe2x80x94NR8R9, xe2x80x94NR10C(Z)R8 (such xe2x80x94NHCO(C1-10 alkyl)); xe2x80x94NR10S(O)mR25 (such as xe2x80x94NHSO2(C1-10 alkyl)); t is 0, or an integer of 1 to 4.
One skilled in the art would readily recognize that when R2 is a (CR10R20)nOC(Z)R13, or (CR10R20)nOC(Z)NR8R9 moiety, or any similarly substituted group that n is preferably at least 2 which will allow for the synthesis of stable compounds.
Preferably R2 is a C1-4 alkyl (branched and unbranched), a methylthio propyl, a methylsulfinyl propyl, an amino propyl, N-methyl-N-benzylamino propyl group, diethylamino propyl, cyclopropyl methyl, morpholinyl butyl, morpholinyl propyl, a morpholinyl ethyl, a piperidine or a substituted piperidine. More preferably R2 is isopropyl; butyl; t-butyl; n-propyl; methylthiopropyl or methylsulfinyl propyl; morpholino propyl; morpholinyl butyl; phenyl substituted by halogen, thioalkyl or sulfinyl alkyl such as a methylthio, methylsulfinyl or methylsulfonyl moiety; piperidinyl; 1-Formyl-4-piperidine; 1-benzyl-4-piperidine; 1-methyl-4-piperidine, or a 1-ethoxycarbonyl-4-piperidine.
Suitably, R3 is xe2x80x94XaP(Z)(XbR13)2 or Qxe2x80x94(Y1)t. Preferably, the R3 moiety is Qxe2x80x94(Y1)t and Q is an (un)substituted aryl or heteroaryl moiety. Preferably, when Q is an aryl, it is phenyl, and when Q is a heteroaryl, preferred groups include thienyl, pyrrole, pyridine, or pyrimidine. More preferred Q is phenyl. Q is independently substituted 1 to 3 times by Y1. Preferably t is 1 or 2. More preferably, when R3 is mono-substituted phenyl, the substituent is located at the 4-position.
Preferably Q is substituted by 1 or 2 substituents which include halogen, C1-5 alkyl and xe2x80x94(CR10R20)nY2 wherein Y2 is xe2x80x94OR8, xe2x80x94NO2, xe2x80x94S(O)mxe2x80x2R11, xe2x80x94SR8, xe2x80x94S(O)mNR8R9; xe2x80x94NR8R9, xe2x80x94O(CR10R20)nNR8R9, xe2x80x94C(O)R8, xe2x80x94CO2(CR10R20)nxe2x80x2CONR8R9, xe2x80x94CN; xe2x80x94C(Z)NR8R9, xe2x80x94NR10S(O)mR11, xe2x80x94NR10C(Z)R8, xe2x80x94NR10(C(Z)NR8R9, xe2x80x94C(Z)NR8OR9, xe2x80x94N(OR21)C(Z)NR8R9, xe2x80x94NR10C(xe2x95x90NR15)NR8R9, xe2x80x94C(xe2x95x90NOR13)NR8R9, 5-(R18)-1,2,4-oxadizaol-3-yl and 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl.
Preferred substituents Y1 for use in R3 when the aryl or heteroaryl group Q is mono-substituted include xe2x80x94(CR10R20)nY2 wherein: n is 0, 1, 2 or 3, preferably 0 or 1; and Y2 is xe2x80x94OR8, especially where R8 is hydrogen or C1-10 alkyl; xe2x80x94NO2; xe2x80x94S(O)mxe2x80x2R11, especially where R11 is C1-10 alkyl; xe2x80x94SR8, especially where R8 is C1-10 alkyl; xe2x80x94S(O)mNR8R9, especially where R8 and R9 is each hydrogen or C1-10 alkyl or R8 and R9 together with the nitrogen to which they are attached form a 5 to 7 membered ring which optionally includes another heteroatom selected from oxygen, sulfur or NR12 and m is 2; nxe2x80x2 is 1 to 10; xe2x80x94NR8R9, especially where R8 and R9 is each hydrogen methyl or benzyl or R8 and R9 together with the nitrogen to which they are attached form a 5 to 7 membered ring which optionally includes another heteroatom selected from oxygen, sulfur or NR12; xe2x80x94O(CR10R20)nNR8R9, especially where R8 and R9 is each C1-10 alkyl; xe2x80x94C(O)R8, especially where R8 is hydrogen or C1-10 alkyl; xe2x80x94CO2R8, especially where R8 is hydrogen or C1-10 alkyl; xe2x80x94CO2(CR10R20)nxe2x80x2CONR8R9, especially where R8 and R9 is hydrogen or C1-10 alkyl; xe2x80x94CN; xe2x80x94C(Z)NR8R9, especially where R8 and R9 is hydrogen or C1-10 alkyl; xe2x80x94NR10S(O)mR11, especially where R10 is hydrogen or C1-10 alkyl and R11 is C1-10 alkyl or a halosubstituted ; xe2x80x94NR10C(Z)R8, especially where R8 is C1-10 alkyl and R10 is hydrogen and Z is oxygen; xe2x80x94C(Z)NR8OR9, especially where R8 and R9 is each hydrogen and Z is oxygen; xe2x80x94NR10C(Z)NR8R9, especially where R8 and R9 is each hydrogen or C1-10 alkyl and Z is oxygen; xe2x80x94N(OR21)C(Z)NR8R9, especially where R8 especially where R8, R9 and R21 is each hydrogen or C1-10 alkyl and Z is oxygen; xe2x80x94C(xe2x95x90NOR13)NR8R9, especially where R8, R9 and R13 is each hydrogen; xe2x80x94NR10C(xe2x95x90NR15)NR8R9, especially where R8 and R9 is hydrogen, C1-10 alkyl or arylalkyl and R15 is cyano; and 5-(R18)-1,2,4-oxadizaol-3-yl and 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl, especially where R12 is hydrogen and R18 and R19 is each hydrogen or C1-10 alkyl or together are oxo.
Preferred substituents for use in R3 when the aryl or heteroaryl group Q is disubstituted include those hereinbefore listed for use when Q is mono-substituted and, as further substituent(s), halogen and C1-10 alkyl. When R3 is phenyl substituted with two or three substituents, the alkyl moieties preferably have from one to three carbons, more preferably one. Preferred ring positions for two substituents are the 3-and 4-positions and, for three substituents, the 3-, 4-and 5-positions. The substituent at the 3-and 5-positions is preferably C1-2 alkyl, such as methyl, or halogen, such as bromo, fluoro or chloro, while the substituent at the 4-position is preferably hydroxyl.
More preferably, for R3 substituents wherein Y1 is (CR10R20)nY2, n is 0 or 1 and Y2 is xe2x80x94OH, xe2x80x94S(O)mxe2x80x2R11, especially where R11 is C1-10 alkyl; xe2x80x94SR8, especially where R8 is C1-10 alkyl; xe2x80x94NR8R9, especially where R8 and R9 is hydrogen, alkyl, aryl alkyl, or aryl or R8 and R9 together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring, more prefereably the R8 and R9 terms in the NR8R9 moiety are hydrogen, methyl or benzyl; xe2x80x94CO2R8, especially where R8 is hydrogen or C1-10 alkyl; xe2x80x94S(O)mxe2x80x2NR8R9, especially where R8 and R9 is each hydrogen or C1-10 alkyl; xe2x80x94NR10S(O)mR11, especially where R10 is hydrogen and R11 is C1-10 alkyl or 5-(R18)-1,2,4-oxadizaol-3-yl and 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4oxadiazol-3yl, especially where R12 is hydrogen and R18 and R19 is hydrogen or C1-10 alkyl or together are oxo.
Most preferably, Y1 is methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, N,N-dimethylaminomethyl, N-benzyl-N-methylaminomethyl, N-morpholinomethyl, methanesulfonamido, sulphonamidomethyl, 5-methyl-4,5-dihydro-1,2,4-oxadiazol-3-yl or 5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl.
In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, such as in R5, R8, R9, or R11 the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to the nitrogen, oxygen or sulfur moieties, for instance in Y2 as C(Z)NR8OR9, NR10C(Z)NR8R9, or OR8.
As used herein, xe2x80x9coptionally substitutedxe2x80x9d unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted C1-10 alkyl; C1-10 alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1 or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl; amino, mono and di-substituted amino, such as in the NR7R17 group; or where the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S; C1-10 alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted C1-10 alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties may also be substituted one to two times by halogen, hydroxy, hydroxy substituted alkyl, C1-10 alkoxy, S(O)m alkyl, amino, mono and di-substituted amino, such as in the NR7R17 group, C1-10 alkyl, or CF3.
When R3 includes a Xaxe2x80x94P(Z)(XbR13)2 group linked either directly to the imidazole ring or indirectly via an aryl or heteroaryl group, Xa is suitably oxygen or C1-4 alkylene, optionally interupted by oxygen, for instance xe2x80x94CH2OCH2xe2x80x94 and Z and Xb is each oxygen, such that the preferred groups include xe2x80x94OP(O)(OR13)2 and xe2x80x94CH2OCH2xe2x80x94P(O)(OR13)2.
Preferred substitutions for R4 when it is a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl moiety are one or two substituents each independently selected from halogen, xe2x80x94SR5, xe2x80x94SOR5, xe2x80x94OR36, or xe2x80x94(CR10R20)mNR10R20, and for other positions of substitution on these rings preferred substitution is halogen, xe2x80x94S(O)mR8, xe2x80x94OR8, xe2x80x94(CR10R20)mNR16R26, xe2x80x94NR10C(Z)R8 and xe2x80x94NR10S(O)mR11. More preferred substituents for the 4-position in phenyl and naphth-1-yl and on the 5-position in naphth-2-yl include halogen, especially fluoro and chloro, and xe2x80x94SR5 and xe2x80x94SOR5 wherein R5 is preferably a C1-2 alkyl, more preferably methyl; of which fluoro is especially preferred. Preferred substituents for the 3-position in phenyl and naphth-1-yl include: halogen, especially chloro; xe2x80x94OR8, especially C1-4 alkoxy; amino; xe2x80x94NR10C(Z)R8, especially xe2x80x94NHCO(C1-10 alkyl); and xe2x80x94NR10S(O)mR11, especially xe2x80x94NHSO2(C1-10 alkyl). Preferably, the R4 moiety is an unsubstituted or substituted phenyl moiety. More preferably, R4 is phenyl or phenyl substituted at the 4-position with fluoro and/or substituted at the 3-position with fluoro, chloro, C1-4 alkoxy, methanesulfonamido or acetamido.
A preferred grouping of formula (I) are those compounds wherein R2 is an optionally substituted C1-10 alkyl, optionally substituted C3-7cycloalkyl, or an optionally substituted C3-7cycloalkyl C1-10 alkyl, an optionally substituted aryl, an optionally substituted heterocyclic alkyl, an optionally substituted heterocyclic, optionally substituted heteroaryl or heteroarylalkyl, (CR10R20)nxe2x80x2OR13, (CR10R20)nxe2x80x2S(O)mR25, (CR10R20)nxe2x80x2NR8R9, (CR10R20)nxe2x80x2C(Z)OR13, (CR10R20)nxe2x80x2NHS(O)2R25, (CR10R20)nxe2x80x2C(Z)R13, or (CR10R20)nxe2x80x2C(xe2x95x90NOR21)R13; and R1, R3, and R4 are as defined for Formula (I).
More preferred are those compounds wherein R2 is a C1-4 alkyl (branched and unbranched), such as isopropyl, butyl, t-butyl, n-propyl, a methylthio propyl, a methylsulfinyl propyl, an amino propyl, N-methyl-N-benzylamino propyl group, (phenylmethyl)amino-1-propyl, diethylamino propyl, cyclopropyl methyl, morpholinyl butyl, morpholinyl propyl, morpholinyl ethyl, 1-Formyl-4-piperidinyl, 1-benzyl-4-piperidinyl, 1-methyl-4-piperidinyl, 1-ethoxycarbonyl-4-piperidinyl, phenyl substituted by halogen, thioalkyl or sulfinyl alkyl such as a methylthio, methylsulfinyl or methylsulfonyl moiety; and R1, R3, and R4 are as defined for Formula (I).
Further preferred compounds of Formula (I) are those wherein R1 is an optionally substituted 4-pyridyl or pyrimidinyl; and more preferably R4 is a 2-methyl-4-pyridyl or 2-amino-pyrimidinyl.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent Y1 in R3 comprises a carboxy group. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quarternary ammonium cations.
The following terms, as used herein, refer to:
xe2x80x9chaloxe2x80x9dxe2x80x94all halogens, that is chloro, fluoro, bromo and iodo;
xe2x80x9cC1-10 alkylxe2x80x9d or xe2x80x9calkylxe2x80x9dxe2x80x94both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like;
The term xe2x80x9ccycloalkylxe2x80x9d is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The term xe2x80x9ccycloalkenylxe2x80x9d is used herein to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one bond including but not limited to cyclopentenyl, cyclohexenyl, and the like.
xe2x80x9carylxe2x80x9dxe2x80x94phenyl and naphthyl;
xe2x80x9cheteroarylxe2x80x9d (on its own or in any combination, such as xe2x80x9cheteroaryloxyxe2x80x9d)xe2x80x94a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole;
xe2x80x9cheterocyclicxe2x80x9d (on its own or in any combination, such as xe2x80x9cheterocyclylalkylxe2x80x9d)xe2x80x94a saturated or wholly or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine or pyrazolidine;
xe2x80x9caroylxe2x80x9dxe2x80x94a C(O)Ar, wherein Ar is as phenyl, naphthyl, or aryl alkyl derivative such as defined above, such group include but are note limited to benzyl and phenethyl;
xe2x80x9calkanoylxe2x80x9dxe2x80x94a C(O)C1-10 alkyl wherein the alkyl is as defined above;
xe2x80x9csulfinylxe2x80x9dxe2x80x94the oxide S(O) of the corresponding sulfide, while the term xe2x80x9cthioxe2x80x9d refers to the sulfide;
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cheterocyclicalkylxe2x80x9d is used herein to mean an aryl, heteroaryl or heterocyclic moiety as respectively defined above said group connected to C1-6 alkyl group as also defined above unless otherwise indicated.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included within the scope of the present invention.
For the purposes herein of nomenclature, the compounds of formula (I) are named by their position corresponding to: 
Exemplified compounds of formula (I) include:
2-(4-Cyanophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
1-Methyl-2-(4-methoxyphenyl)-4-phenyl-5-(4-pyridyl)-imidazole
2-(4-Cyanophenyl)-1-methyl-4-phenyl-5(4-pyridyl)imidazole
2-(4-Aminomethylphenyl)-1-methyl-4-phenyl-5-(4-pyridyl)-imidazole
4-[1-Methyl-4-phenyl-5(4-pyridyl)-imidazol-2-yl]benzoic acid, sodium salt
2-(4-Acetamidomethyphenyl)-1-methyl-4-phenyl-5-(4-pyridyl)imidazole
Methyl-4-[1-methyl-4-phenyl-5-(4-pyridyl)-imidazol-2-yl]benzoate
4-(4-Fluorophenyl)-N-1-hydroxy-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole
4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoic acid
2-(4-Cyanophenyl)-4-(4-fluorophenyl)-1-N-hydroxy-5-(4-pyridyl)imidazole
2-(4-Aminomethylphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
2-(4-Cyanophenyl)-4-(4-fluorophenyl)-N-1-hydroxy-5-(4-quinolyl)imidazole
2-(4-Cyanophenyl)-4-(4-fluorophenyl)-5-(4-quinolyl)-1H-imidazole
2-(3,5-Dibromo-4-hydroxyphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
Ethyl 4-[4-(4-Fluorophenyl)-5-(4-pyridyl)]-1H-imidazol-2-yl]-benzoate
2-[3,5-Dimethyl-4-hydroxy(phenyl)]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl-2-(2-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole
Methyl 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzoate
4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole
N,N-Dimethyl-4-[4-(4-fluorophenyl-5-(4-pyridyl)-1H-imidazol-2-yl]-benzamide
2-[(4-N,N-Dimethyl)aminomethylphenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
2-[4-(Dimethylamino)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-phenyl-5-(4-pyridyl)-1H-imidazole
2-[4-(3-Dimethylaminopropoxy)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole
N,N-Dimethyl-4-[2-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoyloxyacetamide
2-(4-Aminophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-methanesulfonamidophenyl)-5-(4-pyridyl)-1H-imidazole
4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-sulfonamide
Nxe2x80x2-Cyano-N-4-[4-(fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzylguanidine
2-[4-(Methanesulfonamido)methylphenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-5-(4-pyridyl)-1H-imidazole
2-(4-Amino-3-iodophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
N-Benzyl-N-methyl-4-[4-(4-fluorophenyl-5-(4-pyridyl)-1H-imidazol-2-yl]benzamide
2-[4-(N-Benzyl-N-methyl)aminomethylphenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-N-1-hydroxy-2-(4-methylthiophenyl)-5-(4-quinolyl)imidazole
4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-quinolyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-quinolyl)-1H-imidazole
4-(3-Chlorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole
4-(3-Chlorophenyl)-N-1-hydroxy-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole
4-(3-Chlorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-formamidomethylphenyl)-5-(4-pyridyl)-1H-imidazole
4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzohydroxamic acid
O-Benzyl-4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzohydroxamic acid
4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzamidoxime
Nxe2x80x3-Methyl-Nxe2x80x2-cyano-N-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzylguanidine
N-1-Hydroxy-4-(3-methoxyphenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole
4-(3-Methoxyphenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)imidazole
4-(3-Methoxyphenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole
Morpholino-4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzamide
4-(4-Fluorophenyl)-5-[4-(2-methylpyridyl)]-2-(4-methylthiophenyl)-1H-imidazole
4-(4-Fluorophenyl)-5-[4-(2-methylpyridyl)]-2-(4-methylsulfinylphenyl)-1H-imidazole
4-(4-Fluorophenyl)-N-1-hydroxy-5-(4-pyrimidinyl)-imidazole
4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyrimidinyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-methylsulfinylpheny)-5-(4-pyrimidinyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-methylsulfonylpheny)-5-(4-pyrimidinyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-Morpholinomethylphenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-hydroxymethyl)-5-(4-pyridyl)-1H-imidazole
4-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-benzaldehyde
4-(2-Methoxyphenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole
N-1-Hydroxy-4-(2-methoxyphenyl)-2-(4-methylthio-phenyl)-5-(4-pydidyl)imidazole
4-(2-Methoxyphenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole
3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-5-methyl-4,5-dihydro-1,2,4-oxadiazole
3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-5-methyl-1,2,4-oxadiazole
4-(3-Aminophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole
N-1-Hydroxy-2-(4-methylthiophenyl)-4-(3-nitrophenyl)-5-(4-pyridyl)imidazole
2-(4-Methylthiophenyl)-4-(3-nitrophenyl)-5-(4-pyridyl)-1H-imidazole
4-(3-Methanesulfonamidophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole
3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl-1,2,4-oxadiazol-5-(4H)-one
4-(3-Acetamidophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-1-N-hydroxy-5-[4-(2-methylpyridyl)]-2-(4-methylthiophenyl)-imidazole
3-[4-(4-Fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]-phenyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazole
N-Hydroxy-N-1-[4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl]ethyl]urea
N-Hydroxy-N-[4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]phenyl]-methyl urea
4-(3-Methylthiophenyl)-2-(4-morpholinomethylphenyl)-5-(4-pyridyl)-1H-imidazole
4-(3-Methylsulfinylphenyl)-2-(4-morpholinomethylphenyl)-5-(4-pyridyl)-1H-imidazole
4-(3-Methanesulfonamidophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole
2-(4-Ethylthiophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
2-(4-Ethylsulfinylphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-[(4-(4-methyl-1-piperzinyl)-sulfonyl-phenyl]-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-[4-(N-methylmethanesulfonamido)-methylphenyl]-5-(4-pyridyl)-1H-imidazole
Diethyl [1-methyl-4-phenyl-5-(4-pyridyl)-imidazol-2-yl]methoxy]methylphosphonate
4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(3-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(3-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-5-(4-pyridyl)imidazole
4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-1-(N-morpholinopropyl)-5-(4-pyridyl)imidazole
4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-1-(N-morpholinopropyl)-5-(4-pyridyl)imidazole
4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-1-(N-morpholinopropyl)-5-(4-pyridyl)imidazole
4-(4-Fluorophenyl)-1-(methylthio-1-propyl)-2-([4-N-morpholinomethyl]phenyl)-5-(4-pyridyl)imidazole
4-(4-Fluorophenyl)-1-(methylsulfinyl-1-propyl)-2-([4-N-morpholinomethyl]phenyl)5-(4-pyridyl)imidazole
4-(4-Fluorophenyl)-1-(methylsulfonyl-1-propyl)-2-([4-N-morpholinomethyl]phenyl)-5-(4-pyridyl)imidazole
and pharmaceutically acceptable salts thereof.
Compounds of formula (I) are imidazole derivatives which may be readily prepared using procedures well-known to those skilled in the art, and described in, for instance, Comprehensive Heterocyclic Chemistry, ed Katritzky and Rees, Pergamon Press, 1984, 5, 457-497, from starting materials which are either commercially available or can be prepared from such by analogy with well-known processes. A key step in many such syntheses is the formation of the central imidazole nucleus, to give compounds of formula (I). Suitable procedures are described in inter alia U.S. Pat. Nos. 3,707,475 and 3,940,486 which are herein incorporated by reference in their entirety. These patents describe the synthesis of a-diketones and a-hydroxyketones (benzoins) and their subsequent use in preparing imidazoles and N-hydroxyl imidazoles. Thereafter, further compounds of formula (I) may be obtained by manipulating substituents in any of the groups R1, R2, R3 and R4 using conventional functional group interconversion procedures.
In particular, in a first process, compounds of formula (I) may be prepared by condensing an xcex1-diketone of formula (II):
R1COCOR4xe2x80x83xe2x80x83(I)
wherein R1 and R4 are as hereinbefore defined, or an equivalent thereof, with an aldehyde of the formula (III):
R3CHOxe2x80x83xe2x80x83(III)
wherein R3 is as hereinbefore defined, or an equivalent thereof, and, if necessary, with ammonia or a source thereof, under imidazole-ring forming conditions.
Suitable equivalents of the xcex1-diketone are well known to those skilled in the art and include the corresponding xcex1-keto-oxime and xcex1-dioxime. Suitable equivalents of the aldehyde of formula (III) are well known in the art and include the corresponding oxime and acetal.
Ammonia, or a source thereof, is preferably used in excess, with at least a dimolar amount being used in the case of the xcex1-diketone and at least an equimolar amount in the case of the xcex1-keto-oxime.
Suitable sources of ammonia include ammonium salts of organic carboxylic acids, such as an ammonium C1-6 alkanoate, for instance ammonium acetate and ammonium formate, preferably ammonium acetate, and carboxylic amides, in particular of formic acid, such as formamide. An ammonium salt is generally used in large excess and in the presence of an acid, such as a C1-6 carboxylic acid which acid may also be used as a solvent for the reaction. If formamide is used, this may be used in excess, as the reaction solvent. An alternative solvent such as ethanol or dimethyl sulphoxide (Lantos et al, J Het Chem, 19, 1375, 1982) may be used. An additional solvent may also be employed, for instance, dimethyl formamide may be used with formamide. The reaction is generally carried out at elevated temperatures, for instance under reflux conditions, and if desired, in a sealed vessel optionally under pressure and/or an inert gas atmosphere, for instance nitrogen.
A further suitable source of ammonia is hydroxylamine, in which case the initially formed imidazole is an N-hydroxy-N-oxide imidazole. This may then be reduced to the corresponding N-hydroxy imidazole by treating with a suitable reducing agent such as sodium borohydride, in an appropriate solvent such as methanol, following the method of Akange and Allan, Chem and Ind, Jan. 5, 1975, 38. The N-hydroxy imidazole may in turn be converted to an imidazole of formula (I) in which R2 is hydrogen by treatment with a conventional deoxygenating agent such as phosphorus trichloride or a trialkylphosphite such as trimethyl- or triethyl-phosphite. N-hydroxy-N-oxide imidazoles may be readily obtained by treating an xcex1-diketone of formula (II) with an aldehyde of formula (II) with about two equivalents of hydroxylamine or the corresponding aldoxime and about one equivalent of hydroxylamine, under proton catalysis. Alternatively, the N-oxide may be obtained by the acid catalysed condensation of the corresponding xcex1-dioxime or xcex1-keto-oxime with an aldoxime of the aldehyde of formula (III).
When the compound of formula (II) is an xcex1-keto-oxime derivative, it will be appreciated that the product initially obtained will be a compound of formula (I) in which R2 is hydroxyl which may be converted into a compound of formula (I) in which R2 is hydrogen as described above.
It will be appreciated by those skilled in the art that in some instances, it will not be necessary to provide a separate source of ammonia as the xcex1-diketone or aldehyde equivalent may already contain such a source. Examples of this include xcex1-dioxime or xcex1-keto-oxime and aldoxime.
The compounds of formula (II) may be obtained by applying well-known synthetic procedures, some of which are illustrated in schemes I and II. Although these illustrate syntheses in which R4 is either 4-pyridyl or 4-quinolinyl, they may be equally applied to any of the other heteroaryl rings within the definition of R4 by appropriate choice of starting material.
In Scheme I, the anion prepared from 1, by treatment with a strong base such as lithium di-iso-propylamide, is condensed with a substituted benz-aldehyde, to give, after removal of the protecting group, the diol 2. This may then be converted to the a-diketone 3 by a Swern oxidation of which any number of potentially useful variations are known and may be used. The a-diketone 3 is then cyclised to an imidazole 4, a compound of formula (I), by heating 3 with a substituted benzaldehyde in a mixture of ammonium acetate, as the source of ammonia, and an appropriate solvent, for example acetic acid or DMSO. The imidazole 4 may then be transformed into other imidazoles 5 by appropriate functional group interconversion procedures. Scheme I also illustrates the preparation of a protected xcex1-hydroxyketone 2a, by condensing the anion of 1 with an appropriately activated carbonyl derivative of a substituted benzamide, such as the N-methoxy-N-methylamide, to yield a protected a-hydroxyketone. This adduct 2a may then be directly converted to the imidazole 5, using a combination of a copper (II) salt, such as copper (II) acetate, as an oxidising agent and ammon-ium acetate as a source of ammonia. The xcex1-hydroxyketone 2a may also be deprotected and then oxidised to give an a-diketone 3, for instance using Swern oxidation. 
Scheme II illustrates the use of an a-keto-oxime for preparing a compound of formula (I). A heterocyclic ketone 7 is prepared by adding the anion of 4-methyl-quinoline (prepared by treatment thereof with an alkyl lithium, such as n-butyl lithium) to an N-alkyl-O-alkoxybenzamide. Alternatively, the anion may be condensed with a benzaldehyde, to give an alcohol which is then oxidised to the ketone 7. The xcex1-keto-oxime 8 is then prepared from 7 using standard conditions, such as reaction with sodium nitrite, and this may then be reacted with a benzaldehyde to afford an N-hydroxyimidazole 9, a compound of formula (I) in which R2 is hydroxy. This may converted to 10, a further compound of formula (I) in which R2 is hydrogen, by treating it with a deoxygenating agent such as phosphorus trichloride or a trialkyl phosphite, such as trimethyl or triethylphosphite. For compounds of formula (I) wherein R3 is xe2x80x94(CR10R20)nxe2x80x94P(Z)xe2x80x94(XbR13)2, the reagent OHCxe2x80x94(CR10R20)nxe2x80x94P(Z)xe2x80x94(XbR13)2 may be used instead of OHCxe2x80x94C6H4xe2x80x94X to make the appropriately substituted compound 9. 
In a further process, a compound of formula (I) may be obtained by treating an a-hydroxyketone compound of formula (IIA):
Rxe2x80x2CHOHCORxe2x80x3xe2x80x83xe2x80x83(IIA)
wherein one of Rxe2x80x2 and Rxe2x80x3 is R1 and the other is R4, a suitably protected derivative thereof or the xcex1-hydroxy-oxime or xcex1-haloketone derivative thereof, with an oxidising agent capable of converting said compound into the corresponding a-diketone, in the presence of an aldehyde of formula (III) or an equivalent thereof, and a source of ammonia. Suitable oxidising agents include, for example, an oxidising heavy metal salt, preferably an organic copper (II) salt, such as copper (II) acetate or copper (II) citrate. The reaction may be effected in a solvent such as acetic acid, under reflux conditions. Alternatively, a lower alkanol solvent, such as methanol or ethanol, may be used, preferably at a temperature in the region of from 30 to 100xc2x0 C. (see The Chemistry of Heterocyclic Compounds, Imidazole and its derivatives, part I, ed. Weissberger, Interscience Publishers, Inc., New York, 1953, 38). This approach is also illustrated in Scheme I.
In a further process, a compound of formula (I) may be obtained by treatment with a compound of formula (XI) as described later. A compound of Formula (XI) is obtained by treating a compound (an amidine) of formula (IV):
R3C(xe2x95x90NH)NHR2xe2x80x83xe2x80x83(IV)
wherein R2 and R3 are as hereinbefore defined, or a salt thereof, with a reactive ester of an xcex1-hydroxyketone of formula (IIA) or the corresponding xcex1-haloketone, in an inert solvent such as a halogenated hydrocarbon solvent, for example chloroform, at a moderately elevated temperature and, if necessary, in the presence of a suitable condensation agent such as a base. Suitable reactive esters include esters of strong organic acids such as a lower alkane sulphonic or aryl sulphonic acid, for instance, methane or p-toluene sulphonic acid. The amidine of formula (IV) is preferably used as the salt, suitably the hydrochloride salt, which may then be converted into the free amidine in situ, by employing a two phase system in which the reactive ester is in an inert organic solvent such as chloroform, and the salt is in an aqueous phase to which a solution of an aqueous base is slowly added, in dimolar amount, with vigorous stirring. Suitable amidines of formula (IV) may be obtained by standard methods, see for instance, Garigipati R, Tetrahedron Letters, 190, 31, 1989.
Compounds of Formula (IV) wherein R2 is methyl, for instance may be made by the route indicated below. 
In a further process, a compound of formula (I) may be obtained by treating an iminoether of formula (V):
R3Cxe2x95x90NORxe2x80x83xe2x80x83(V)
wherein R3 is as hereinbefore defined and R is C1-10 alkyl, aryl or aryl C1-4 alkyl, with an xcex1-aminoketone of the formula (VI):
Rxe2x80x2CHNH2CORxe2x80x3xe2x80x83xe2x80x83(VI)
wherein one of Rxe2x80x2 and Rxe2x80x3 is R1 and the other is R4 in a suitable solvent.
In a further process, N-substituted compounds of formula (I) may be prepared by treating the anion of an amide of formula (VII):
R1CH2NR2COR3xe2x80x83xe2x80x83(VII)
wherein R1 and R3 are as hereinbefore defined and R2 is as hereinbefore defined other than hydrogen, with:
(a) a nitrile of the formula (VIII):
R4CNxe2x80x83xe2x80x83(VIII)
wherein R4 is as hereinbefore defined, or
(b) an excess of an acyl halide, for instance an acyl chloride, of the formula (IX):
R4COHalxe2x80x83xe2x80x83(IX)
wherein R4 is as hereinbefore defined and Hal is halogen, or a corresponding anhydride, to give a bis-acylated intermediate which is then treated with a source of ammonia, such as ammonium acetate.
This approach permits the regiospecific preparation of compound of formula (I) substituted at the 1-position, as illustrated in Scheme III. A primary amine RNH2 is treated with 4-chloromethylpyridine to give 11 which is then converted to the amide 12 by standard techniques. Deprotonation of 12 with a strong amide base, such as lithium di-iso-propyl amide or sodium bis-(trimethylsilyl)amide, followed by addition of an excess of an aroyl chloride yields the bis-acylated compound 13 which is then closed to an imidazole compound of formula (I), 14, by heating in acetic acid containing ammonium acetate. Alternatively, the anion of 12 may be reacted with a substituted aryl nitrile to produce the imidazole 14 directly. 
In a further process, compounds of formula (I) may be prepared by treating a compound of formula (X):
Rxe2x80x2COCHRxe2x80x3XcCOR3xe2x80x83xe2x80x83(X)
wherein Rxe2x80x2, Rxe2x80x3 and R3 are as hereinbefore defined and Xc is O or NH, with a source of ammonia, as hereinbefore described, under imidazole ring forming conditions or cyclising the corresponding Schiff""s base, formed by treating the compound of formula (X) in which Xc is NH with an amine R2NH2, for instance thermally or with the aid of a cyclising agent such as phosphorus oxychloride or phosphorus pentachloride (see Engel and Steglich, Liebigs Ann Chem, 1978, 1916 and Strzybny et al., J Org Chem, 1963, 28, 3381). Compounds of formula (X) may be obtained, for instance, by acylating the corresponding a-keto-oxime (Xc is NH) or a-hydroxyketone (Xc is O) with an acyl halide of the formula R3COHal wherein R3 is as hereinbefore defined, or the corresponding anhydride, under standard acylating conditions.
In a further process, compounds of formula (I) may be prepared by coupling a suitable derivative of a compound of formula (XI): 
wherein: T2 is a nitrogen protecting group or R2, other than hydrogen; and T1 is hydrogen, T3 is Q and T4 is R4; T1 is R1, T3 is hydrogen and T4 is R4; or T1 is T3 is Q and T4 is hydrogen, in which R1, R2, R3, R4 and Q are as hereinbefore defined; with: (i) when T1 is hydrogen, a suitable derivative of the heteroaryl ring R1H, under ring coupling conditions, to effect coupling of the heteroaryl ring R1 to the imidazole nucleus at position 5; (ii) when T3 is hydrogen, a suitable derivative of the aryl or heteroaryl ring QH, under ring coupling conditions, to effect coupling of the ring Q to the imidazole nucleus at position 2; or (iii) when T4 is hydrogen, a suitable derivative of the aryl ring R4H, under ring coupling conditions, to effect coupling of the aryl ring R4 to the imidazole nucleus at position 4.
Such aryl/heteroaryl coupling reactions are well known to those skilled in the art. In general, an organometallic synthetic equivalent of an anion of one component is coupled with a reactive derivative of the second component, in the presence of a suitable catalyst. The anion equivalent may be formed from either the imidazole of formula (XI), in which case the aryl/heteroaryl compound provides the reactive derivative, or the aryl/heteroaryl compound in which case the imidazole provides the reactive derivative. Accordingly, suitable derivatives of the compound of formula (XI) or the aryl/heteroaryl rings include organometallic derivatives such as organomagnesium, organozinc, organostannane and boronic acid derivatives and suitable reactive derivatives include the the bromo, iodo, fluorosulfonate and trifluoromethanesulphonate derivatives. Suitable procedures are described in WO 91/19497, the disclosure of which is herewith incorporated.
Suitable organomagnesium and organozinc derivatives of a compound of formula (XI) may be reacted with a halogen, fluorosulfonate or triflate derivative of the heteroaryl or aryl ring, in the presence of a ring coupling catalyst, such as a palladium (O) or palladium (II) catalyst, following the procedure of Kumada et al., Tetrahedron Letters, 22, 5319 (1981). Suitable such catalysts include tetrakis-(triphenylphosphine)palladium and PdCl2[1,4-bis-(diphenylphosphino)-butane], optionally in the presence of lithium chloride and a base, such as triethylamine. In addition, a nickel (II) catalyst, such as Ni(II)Cl2(1,2-biphenylphosphino)ethane, may also be used for coupling an aryl ring, following the procedure of Pridgen, J. Org. Chem, 1982, 47, 4319. Suitable reaction solvents include hexamethylphosphor-amide. When the heteroaryl ring is 4-pyridyl, suitable derivatives include 4-bromo- and 4-iodo-pyridine and the fluorosulfonate and triflate esters of 4-hydroxy pyridine. Similarly, suitable derivatives for when the aryl ring is phenyl include the bromo, fluorosulfonate, triflate and, preferably, the iodo-derivatives. Suitable organomagnesium and organozinc derivatives may be obtained by treating a compound of formula (XI) or the bromo derivative thereof with an alkyllithium compound to yield the corresponding lithium reagent by deprotonation or transmetallation, respectively. This lithium intermediate may then be treated with an excess of a magnesium halide or zinc halide to yield the corresponding organometallic reagent.
A trialkyltin derivative of the compound of formula (XI) may be treated with a bromide, fluorosulfonate, triflate, or, preferably, iodide derivative of an aryl or heteroaryl ring compound, in an inert solvent such as tetrahydrofuran, preferably containing 10% hexamethylphosphoramide, in the presence of a suitable coupling catalyst, such as a palladium (0) catalyst, for instance tetrakis-(triphenylphosphine)palladium, by the method described in by Stille, J. Amer. Chem. Soc., 1987, 109, 5478, U.S. Pat. Nos. 4,719,218 and 5,002,942, or by using a palladium (II) catalyst in the presence of lithium chloride optionally with an added base such as triethylamine, in an inert solvent such as dimethyl formamide. Trialkyltin derivatives may be conveniently obtained by metallation of the corres-ponding compound of formula (XI) with a lithiating agent, such as s-butyl-lithium or n-butyllithium, in an ethereal solvent, such as tetrahydrofuran, or treatment of the bromo derivative of the corresponding compound of formula (XI) with an alkyl lithium, followed, in each case, by treatment with a trialkyltin halide. Alternatively, the bromo- derivative of a compound of formula (XI) may be treated with a suitable heteroaryl or aryl trialkyl tin compound in the presence of a catalyst such as tetrakis-(triphenyl-phosphine)palladium, under conditions similar to those described above.
Boronic acid derivatives are also useful. Hence, a suitable derivative of a compound of formula (XI), such as the bromo, iodo, triflate or fluorosulphonate derivative, may be reacted with a heteroaryl- or aryl-boronic acid, in the presence of a palladium catalyst such as tetrakis-(triphenylphosphine)-palladium or PdCl2[1,4-bis-(diphenylphosphino)-butane] in the presence of a base such as sodium bicarbonate, under reflux conditions, in a solvent such as dimethoxyethane (see Fischer and Haviniga, Rec. Trav. Chim. Pays Bas, 84, 439, 1965, Snieckus, V., Tetrahedron Lett., 29, 2135, 1988 and Terashimia, M., Chem. Pharm. Bull., 11, 4755, 1985). Non-aqueous conditions, for instance, a solvent such as DMF, at a temperature of about 100xc2x0 C., in the presence of a Pd(II) catalyst may also be employed (see Thompson W J et al, J. Org. Chem, 49, 5237, 1984). Suitable boronic acid derivatives may be prepared by treating the magnesium or lithium derivative with a trialkylborate ester, such as triethyl, tri-iso-propyl or tributylborate, according to standard procedures.
In such coupling reactions, it will be readily appreciated that due regard must be exercised with respect to functional groups present in the compunds of formula (XI). Thus, in general, amino and sulfur substituents should be non-oxidised or protected and the N-1 nitrogen of a compound of formula (XI) be protected, if an NH compound is finally required. Nitro, bromo, iodo and hydroxyl groups should preferably be avoided in compounds of formula (XI) in which T1 is hydrogen.
Compounds of formula (XI) are imidazoles and may be obtained by any of the procedures herein before described for preparing compounds of formula (I). In particular, an a-halo-ketone R4COCH2Hal (for compounds of formula (XI) in which T1 is hydrogen) or R1COCH2Hal (for compounds of formula (XI) in which T4 is hydrogen) may be reacted with an amidine of formula (IV) or a salt thereof, in an inert solvent such as a halogenated hydrocarbon solvent, for instance chloroform, at a moderately elevated temperature, and, if necessary, in the presence of a suitable condensation agent such as a base. The preparation of suitable a-halo-ketones is described in WO 91/19497. For a compound of formula (XI) in which T3 is hydrogen, an a-diketone of formula (II) may be condensed with a formaldehyde or an equivalent thereof, in the presence of a source of ammonia. Suitable bromo derivatives of the compound of formula (XI) may be obtained by brominating the corresponding compound of formula (XI) under standard brominating conditions, for instance bromine in a solvent such as dichioromethane or THF.
Compounds of formula (I) may also be prepared by a process which comprises reacting a compound of formula (XI), wherein T1 is hydrogen, with an N-acyl heteroaryl salt, according to the method disclosed in U.S. Pat. Nos. 4,803,279, 4,719,218 and 5,002,942, to give an intermediate in which the heteroaryl ring is attached to the imidazole nucleus and is present as a 1,4-dihydro derivative thereof, which intermediate may then be subjected to oxidative-deacylation conditions. The heteroaryl salt, for instance a pyridinium salt, may be either preformed or, more preferably, prepared in situ by adding a substituted carbonyl halide (such as an acyl halide, an aroyl halide, an arylalkyl haloform ate ester, or, preferably, an alkyl haloformate ester, such as acetyl bromide, benzoylchloride, benzyl chloroformate, or, preferably, ethyl chloroformate) to a solution of the compound of formula (XI) in the heteroaryl compound R1H or in an inert solvent such as methylene chloride to which the heteroaryl compound has been added. Suitable deacylating and oxidising conditions are described in U.S. Pat. Nos. 4,803,279, 4,719,218 and 5,002,942, which references are hereby incorporated in their entirety. Suitable oxidising systems include sulfur in an inert solvent or solvent mixture, such as decalin, decalin and diglyme, p-cymene, xylene or mesitylene, under reflux conditions, or, preferably, potassium t-butoxide in t-butanol with dry air or oxygen.
Once the imidazole nucleus has been established, further compounds of formula (I) which may be prepared by applying standard techniques for functional group interconversion, for instance: xe2x80x94C(O)NR8R9 from xe2x80x94CO2CH3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR8R9 in CH3OH; xe2x80x94OC(O)R8 from xe2x80x94OH with e.g.,ClC(O)R9 in pyridine; xe2x80x94NR10xe2x80x94C(S)NR8R9 from xe2x80x94NHR10 with an alkylisothiocyante or thiocyanic acid; NR6C(O)OR6 from xe2x80x94NHR6 with the alkyl chloroformate; xe2x80x94NR10C(O)NR8R9 from xe2x80x94NHR10 by treatment with an isocyanate, e.g. HNxe2x95x90Cxe2x95x90O or R10Nxe2x95x90Cxe2x95x90O; xe2x80x94NR10xe2x80x94C(O)R8 from xe2x80x94NHR10 by treatment with ClC(O)R8 in pyridine; xe2x80x94C(xe2x95x90NR10)NR8R9 from xe2x80x94C(NR8R9)SR8 with H3NR8+OAcxe2x88x92 by heating in alcohol; xe2x80x94C(NR8R9)SR8 from xe2x80x94C(S)NR8R9 with R6xe2x80x94I in an inert solvent, e.g. acetone; xe2x80x94C(S)NR8R9 (where R8 or R9 is not hydrogen) from xe2x80x94C(S)NH2 with HNR8R9, xe2x80x94C(xe2x95x90NCN)xe2x80x94NR8R9 from xe2x80x94C(xe2x95x90NR8R9)xe2x80x94SR8 with NH2CN by heating in anhydrous alcohol, alternatively from xe2x80x94C(xe2x95x90NH)xe2x80x94NR8R9 by treatment with BrCN and NaOEt in EtOH; xe2x80x94NR10xe2x80x94C(xe2x95x90NCN)SR8 from xe2x80x94NHR10 by treatment with (R8S)2Cxe2x95x90NCN; xe2x80x94NR10SO2R8 from xe2x80x94NHR10 by treatment with ClSO2R8 by heating in pyridine; xe2x80x94NR10C(S)R8 from xe2x80x94NR10C(O)R8 by treatment with Lawesson""s reagent [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide]; xe2x80x94NR10SO2CF3 from xe2x80x94NHR6 with triflic anhydride and base; xe2x80x94NR10C(O)xe2x80x94C(O)xe2x80x94OR8 from xe2x80x94NHR10 with, e.g. methyloxalyl chloride and a base such as triethylamine; xe2x80x94NR10C(O)xe2x80x94C(O)xe2x80x94NR8R9 from xe2x80x94NR10C(O)xe2x80x94C(O)xe2x80x94OR8 with HNR8R9; and 1-(NR10)-2-imidazolyl from xe2x80x94C(xe2x95x90NH)NHR10 by heating with 2-chloroacetaldehyde in chloroform (wherein R6, R8, R9 and R10 are as hereinbefore defined). Wherein R6 is C1-4 alkyl, halo-substituted C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or C3-5 cycloalkyl moiety.
Compounds of formula (I) in which R2 is hydrogen may be readily converted into further compounds of formula (I) in which R2 is other than hydrogen, for instance alkyl, by conventional procedures such as alkylation or acylation followed by reduction. Such methods are in general relatively inefficient as they lack regiospecificty and the desired N-1 product has to be separated from the mixture of N-1 and N-3 products, for instance by chromatography or fractional crystallisation.
Compounds of Formula (I) wherein R2 is methyl and R1 is 4-pyridyl or 4-(2-amino)pyrimidinyl for example may be made by the route indicated below. 
Suitable protecting groups for use with hydroxyl groups and the imidazole nitrogen are well known in the art and described in many references, for instance, Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981. Suitable examples of hydroxyl protecting groups include silyl ethers, such as t-butyldimethyl or t-butyldiphenyl, and alkyl ethers, such as methyl connected by an alkyl chain of variable link, (CR10 R20)n. Suitable examples of imidazole nitrogen protecting groups include tetrahydropyranyl.
It should be noted that the compounds of Formula (I),where R4 may be an alkylsulfinyl, arylsulfinyl, alkylsulfonyl, or arylsulfonyl are prodrugs which are reductively converted in vivo to the corresponding alkylthio or arylthio form.
Pharmaceutically acid addition salts of compounds of formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid in the presence of a suitable solvent.
The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.